Arrays for Longitudinal Delivery of TTFields to a Body

ABSTRACT

Tumors in portions of a subject&#39;s body that have a longitudinal axis (e.g., the torso, head, and arm) can be treated with TTFields by affixing first and second sets of electrodes at respective positions that are longitudinally prior to and subsequent to a target region. An AC voltage with a frequency of 100-500 kHz is applied between these sets of electrodes. This imposes an AC electric field with field lines that run through the target region longitudinally. The field strength is at least 1 V/cm in at least a portion of the target region. In some embodiments, this approach is combined with the application of AC electric fields through the target region in a lateral direction (e.g., front to back and/or side to side) in order to apply AC electric fields with different orientations to the target region.

CROSS REFERENCE TO RELATED APPLICATIONS

This Application claims the benefit of U.S. Provisional Application62/356,986 filed Jun. 30, 2016, which is incorporated herein byreference in its entirety.

BACKGROUND

Tumor Treating Fields (TTFields) are low intensity alternating electricfields (e.g., 1-3 V/cm) in the intermediate frequency range (e.g.,125-250 kHz, or in some cases 100-500 kHz) that target solid tumors bydisrupting mitosis. TTFields are typically delivered through two pairsof electrode arrays. The electrode arrays that make up each of thesepairs are positioned on opposite sides of the body part that is beingtreated. FIGS. 1A and 1B depict the conventional positioning ofelectrode arrays on a subject's head and thorax, respectively. In eachof these examples, a first pair of electrode arrays includes oneelectrode array at an anterior position 16/19 and a second electrodearray at a posterior position (not shown, but located directly behindthe corresponding anterior position). When an AC voltage is appliedbetween the anterior electrode array and the posterior electrode array,the field lines of the resulting electric field will run generallybetween the front and the back of the subject.

Each of the FIGS. 1A and 1B examples also includes a second pair ofelectrode arrays including one electrode array at a right-side position14/17 and a second electrode array at a left-side position 15/18. Whenan AC voltage is applied between the right-side array and the left-sidearray, the field lines of the resulting electric field will rungenerally between the left and right sides of the subject. AC voltagesare applied in an alternating sequence between (i) theanterior/posterior (A/P) electrode arrays and (ii) the right/left (R/L)electrode arrays so that the direction of the field will switchrepeatedly (e.g., every 1 sec.) between the two directions describedabove.

While the A/P and R/L electrode arrays are well suited for applyingelectric fields in two roughly perpendicular directions into manyportions of a subject's body, a number of situations can be envisionedin which A/P and R/L electrodes may be difficult or impossible to use.Examples include situations in which a subject has a sore or ulcer atone of the commonly-used sites for positioning an electrode array, aswell as treating tumors at locations where using both A/P and R/Lelectrodes would be uncomfortable and/or impractical (e.g., in asubject's neck, elbow, knee, etc.).

SUMMARY OF THE INVENTION

One aspect of the invention is directed to a first apparatus fortreating a target region in a subject's body with TTFields, the targetregion being located in a portion of the subject's body that has alongitudinal axis. This apparatus comprises a first set of one or morecapacitively coupled electrodes and a first substrate configured to holdthe first set of one or more electrodes against the subject's body sothat the first set of one or more electrodes surrounds a first part ofthe subject's body at a position that is longitudinally prior to thetarget region. This apparatus also comprises a second set of one or morecapacitively coupled electrodes and a second substrate configured tohold the second set of one or more electrodes against the subject's bodyso that the second set of one or more electrodes surrounds a second partof the subject's body at a position that is longitudinally subsequent tothe target region. This apparatus also comprises a third set of one ormore capacitively coupled electrodes and a third substrate configured tohold the third set of one or more electrodes against the subject's bodyon a first side of the target region, at a position that islongitudinally between the first set of one or more electrodes and thesecond set of one or more electrodes. This apparatus also comprises afourth set of one or more capacitively coupled electrodes and a fourthsubstrate configured to hold the fourth set of one or more electrodesagainst the subject's body on a second side of the target region that isopposite to the first side, at a position that is longitudinally betweenthe first set of one or more electrodes and the second set of one ormore electrodes.

Some embodiments of the first apparatus further comprise an AC voltagegenerator configured to generate, in a repeating and alternatingsequence, (a) an AC voltage with a frequency of 100-500 kHz between thefirst set of one or more electrodes and the second set of one or moreelectrodes, and (b) an AC voltage with a frequency of 100-500 kHzbetween the third set of one or more electrodes and the fourth set ofone or more electrodes.

Some embodiments of the first apparatus further comprise an AC voltagegenerator configured to generate, in a repeating and alternatingsequence, (a) an AC voltage with a frequency of 125-250 kHz between thefirst set of one or more electrodes and the second set of one or moreelectrodes, and (b) an AC voltage with a frequency of 125-250 kHzbetween the third set of one or more electrodes and the fourth set ofone or more electrodes.

In some embodiments of the first apparatus, the first set of one or moreelectrodes comprises a first plurality of flat electrode elements, andthe second set of one or more electrodes comprises a second plurality offlat electrode elements. In some of these embodiments, each of the firstand second substrates is flexible.

In some embodiments of the first apparatus, each of the first and secondsubstrates is shaped and dimensioned to fit around the subject's torso.In some embodiments of the first apparatus, the first substrate isshaped and dimensioned to fit around the subject's torso, and the secondsubstrate is shaped and dimensioned to fit around the subject's neck. Insome embodiments of the first apparatus, the first substrate is shapedand dimensioned to fit around the subject's neck, and the secondsubstrate is shaped and dimensioned to fit around the subject's head. Insome embodiments of the first apparatus, the first substrate is shapedand dimensioned to fit around the subject's neck, and the secondsubstrate is shaped and dimensioned to fit on the subject's head. Insome embodiments of the first apparatus, each of the first and secondsubstrates is shaped and dimensioned to fit around the subject's limb.

Some embodiments of the first apparatus further comprise a fifth set ofone or more capacitively coupled electrodes and a fifth substrateconfigured to hold the fifth set of one or more electrodes against thesubject's body on a third side of the target region, at a position thatis longitudinally between the first set of one or more electrodes andthe second set of one or more electrodes. These embodiments also furthercomprise a sixth set of one or more capacitively coupled electrodes anda sixth substrate configured to hold the sixth set of one or moreelectrodes against the subject's body on a fourth side of the targetregion that is opposite to the third side, at a position that islongitudinally between the first set of one or more electrodes and thesecond set of one or more electrodes.

Another aspect of the invention is directed to a first method oftreating a target region in a subject's body with TTFields, the targetregion being located in a portion of the subject's body that has alongitudinal axis. This method comprises affixing a first set of one ormore electrodes to the subject's body so as to surround a first part ofthe subject's body at a position that is longitudinally prior to thetarget region; and affixing a second set of one or more electrodes tothe subject's body so as to surround a second part of the subject's bodyat a position that is longitudinally subsequent to the target region.This method also comprises applying a first AC voltage with a frequencyof 100-500 kHz between the first set of one or more electrodes and thesecond set of one or more electrodes so as to impose a first AC electricfield with field lines that run through the target regionlongitudinally, the first AC electric field having a field strength ofat least 1 V/cm in at least a portion of the target region.

In some embodiments of the first method, each of the first and secondsets of one or more electrodes is capacitively coupled to the subject'sbody.

Some embodiments of the first method further comprise affixing a thirdset of one or more electrodes to the subject's body on a first side ofthe target region, at a position that is longitudinally between thefirst set of one or more electrodes and the second set of one or moreelectrodes, and affixing a fourth set of one or more electrodes to thesubject's body on a second side of the target region that is opposite tothe first side, at a position that is longitudinally between the firstset of one or more electrodes and the second set of one or moreelectrodes. These methods also further comprise applying a second ACvoltage with a frequency of 100-500 kHz between the third set of one ormore electrodes and the fourth set of one or more electrodes so as toimpose a second AC electric field through the target region, the secondAC electric field having a field strength of at least 1 V/cm in at leasta portion of the target region. In some of these embodiments, each ofthe first, second, third, and fourth sets of one or more electrodes iscapacitively coupled to the subject's body. In some of theseembodiments, each of the first and second AC voltages has a frequency of125-250 kHz. In some of these embodiments, the steps of applying thefirst AC voltage and applying the second AC voltage are repeated atleast 10,000 times in an alternating sequence.

Some embodiments of the first method further comprise affixing a fifthset of one or more electrodes to the subject's body on a third side ofthe target region, at a position that is longitudinally between thefirst set of one or more electrodes and the second set of one or moreelectrodes; and affixing a sixth set of one or more electrodes to thesubject's body on a fourth side of the target region that is opposite tothe third side, at a position that is longitudinally between the firstset of one or more electrodes and the second set of one or moreelectrodes. These embodiments also further comprise applying a third ACvoltage with a frequency of 100-500 kHz between the fifth set of one ormore electrodes and the sixth set of one or more electrodes so as toimpose a third AC electric field through the target region, the third ACelectric field having a field strength of at least 1 V/cm in at least aportion of the target region. In some of these embodiments, the steps ofapplying the first AC voltage, applying the second AC voltage, andapplying the third AC voltage are repeated at least 10,000 times in analternating sequence.

In some embodiments of the first method, the first set of one or moreelectrodes comprises a first plurality of flat electrode elementsdistributed around the first part of the subject's body, and the secondset of one or more electrodes comprises a second plurality of flatelectrode elements distributed around the second part of the subject'sbody.

In some embodiments of the first method, the target region is located inthe subject's torso, the first set of one or more electrodes ispositioned around the subject's torso below the target region, and thesecond set of one or more electrodes is positioned around the subject'storso above the target region.

In some embodiments of the first method, the target region is located inthe subject's torso, the first set of one or more electrodes ispositioned around the subject's torso below the target region, and thesecond set of one or more electrodes is positioned around the subject'sneck.

In some embodiments of the first method, the target region is located inthe subject's head, the first set of one or more electrodes ispositioned around the subject's neck, and the second set of one or moreelectrodes is positioned around the subject's head.

In some embodiments of the first method, the target region is located inthe subject's limb. In these embodiments, the longitudinal axis runsthrough the limb in a proximal to distal direction, the first set of oneor more electrodes is positioned around the limb at a position proximalto the target region, and the second set of one or more electrodes ispositioned around the limb at a position distal to the target region.

Another aspect of the invention is directed to a second apparatus fortreating a target region in a limb of a subject's body with TTFields.This apparatus comprises a first set of one or more capacitively coupledelectrodes, and a first substrate configured to hold the first set ofone or more electrodes against the subject's body so that the first setof one or more electrodes partially surrounds a first side of the limbat a position that is proximal to the target region. This apparatus alsocomprises a second set of one or more capacitively coupled electrodes,and a second substrate configured to hold the second set of one or moreelectrodes against the subject's body so that the second set of one ormore electrodes partially surrounds a second side of the limb at aposition that is distal to the target region. The second side of thelimb is opposite to the first side of the limb. This apparatus alsocomprises a third set of one or more capacitively coupled electrodes,and a third substrate configured to hold the third set of one or moreelectrodes against the subject's body so that the third set of one ormore electrodes partially surrounds the second side of the limb at aposition that is proximal to the target region. This apparatus alsocomprises a fourth set of one or more capacitively coupled electrodes,and a fourth substrate configured to hold the fourth set of one or moreelectrodes against the subject's body so that the fourth set of one ormore electrodes partially surrounds the first side of the limb at aposition that is distal to the target region.

Some embodiments of the second apparatus further comprise an AC voltagegenerator configured to generate, in a repeating and alternatingsequence, (a) a first AC voltage with a frequency of 100-500 kHz betweenthe first set of one or more electrodes and the second set of one ormore electrodes, and (b) a second AC voltage with a frequency of 100-500kHz between the third set of one or more electrodes and the fourth setof one or more electrodes. In some of these embodiments, each of thefirst and second AC voltages has a frequency of 125-250 kHz.

In some embodiments of the second apparatus, each of the first, second,third, and fourth sets of one or more electrodes comprises a pluralityof flat electrode elements. In some of these embodiments, each of thefirst, second, third, and fourth substrates is flexible.

In some embodiments of the second apparatus, the limb is an arm, each ofthe first and third substrates is shaped and dimensioned to fit on thearm proximally with respect to the elbow, and each of the second andfourth substrates is shaped and dimensioned to fit on the arm distallywith respect to the elbow. In some embodiments of the second apparatus,the limb is a leg, each of the first and third substrates is shaped anddimensioned to fit on the leg proximally with respect to the knee, andeach of the second and fourth substrates is shaped and dimensioned tofit on the leg distally with respect to the knee.

Another aspect of the invention is directed to a second method oftreating a target region in a limb of a subject's body with TTFields.This method comprises affixing a first set of one or more electrodes soas to partially surround a first side of the limb at a position that isproximal to the target region, and affixing a second set of one or moreelectrodes so as to partially surround a second side of the limb at aposition that is distal to the target region, wherein the second side ofthe limb is opposite to the first side of the limb. This method alsocomprises affixing a third set of one or more electrodes so as topartially surround the second side of the limb at a position that isproximal to the target region, and affixing a fourth set of one or moreelectrodes so as to partially surround the first side of the limb at aposition that is distal to the target region. This method also comprisesapplying a first AC voltage with a frequency of 100-500 kHz between thefirst set of one or more electrodes and the second set of one or moreelectrodes so as to impose a first AC electric field through the targetregion, the first AC electric field having a field strength of at least1 V/cm in at least a portion of the target region; and applying a secondAC voltage with a frequency of 100-500 kHz between the third set of oneor more electrodes and the fourth set of one or more electrodes so as toimpose a second AC electric field through the target region, the secondAC electric field having a field strength of at least 1 V/cm in at leasta portion of the target region. In this method, the steps of applyingthe first AC voltage and applying the second AC voltage are performed ina repeating and alternating sequence.

In some embodiments of the second method, each of the first, second,third, and fourth sets of one or more electrodes is capacitively coupledto the subject's body. In some of these embodiments, each of the firstand second AC voltages has a frequency of 125-250 kHz.

In some embodiments of the second method, the steps of applying thefirst AC voltage and applying the second AC voltage are repeated atleast 10,000 times in an alternating sequence.

In some embodiments of the second method, the limb is an arm, the firstset of one or more electrodes and the third set of one or moreelectrodes are positioned proximally with respect to the elbow, and thesecond set of one or more electrodes and the fourth set of one or moreelectrodes are positioned distally with respect to the elbow. In someembodiments of the second method, the limb is a leg, the first set ofone or more electrodes and the third set of one or more electrodes arepositioned proximally with respect to the knee, and the second set ofone or more electrodes and the fourth set of one or more electrodes arepositioned distally with respect to the knee.

In some embodiments of the second method, each of the first, second,third, and fourth sets of one or more electrodes comprises a pluralityof flat electrode elements.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A and 1B depict the conventional positioning of electrode arrayson a subject's head and thorax, respectively.

FIG. 2 is a schematic illustration depicting how longitudinal pairs ofelectrodes can be used to generate longitudinal electric fields in acylindrical body.

FIG. 3A depicts the positioning of longitudinal pairs of electrodearrays for delivering electric fields to the thorax or abdomen.

FIG. 3B depicts the positioning of longitudinal pairs of electrodearrays for delivering electric fields to the abdomen.

FIG. 3C depicts the positioning of longitudinal pairs of electrodearrays for delivering electric fields to a portion of the arm.

FIG. 3D depicts the positioning of longitudinal pairs of electrodearrays for delivering electric fields to a portion of the leg.

FIG. 3E depicts the positioning of longitudinal pairs of electrodearrays for delivering electric fields to the infratentorial brain, thebrain stem, and to the neck.

FIG. 3F depicts another embodiment for delivering electric fields to theinfratentorial brain, the brain stem, and to the neck.

FIGS. 4A and 4B depict front and back views, respectively, of combininga pair of longitudinal arrays with a pair of anterior/posteriorlatitudinal arrays for delivering fields to the thorax or abdomen.

FIGS. 4C and 4D depict front and back views, respectively, of combininga pair of longitudinal arrays with a pair of left/right latitudinalarrays for delivering fields to the thorax or abdomen.

FIGS. 4E and 4F depict front and back views, respectively, of combininga pair of longitudinal arrays with a pair of diagonally positionedlatitudinal arrays for delivering fields to the thorax.

FIG. 4G depicts a rear view of combining a pair of longitudinal arrayswith a pair of left/right latitudinal arrays for delivering fields tothe infratentorial brain.

FIG. 4H depicts a rear view of another embodiment for combininglongitudinal arrays with latitudinal arrays for use at the same anatomiclocations as FIG. 4G.

FIGS. 5A and 5B depict front and back views, respectively, of combininga pair of longitudinal arrays with both anterior/posterior latitudinalarrays and left/right latitudinal arrays for delivering fields to thethorax.

FIGS. 5C and 5D depict front and back views, respectively, of combininga pair of longitudinal arrays with two pairs of diagonally positionedlatitudinal arrays for delivering fields to the thorax.

FIG. 6A depicts a first configuration that is suitable for affixing aband or belt-shaped set of electrodes to a subject's body.

FIG. 6B depicts a second configuration that is suitable for affixing apanel-shaped set of electrodes to a subject's body.

FIGS. 7A and 7B depict front and back views, respectively of thepositioning of a plurality of electrode elements for one example of apair of longitudinal arrays.

FIGS. 7C and 7D depict front and back views, respectively of thepositioning of a plurality of electrode elements for one example of apair of anterior/posterior latitudinal arrays.

FIGS. 7E and 7F depict front and back views, respectively of thepositioning of a plurality of electrode elements for one example of apair of left/right latitudinal arrays.

FIG. 8 depicts the strength of the electric field for six axial slicesusing the FIG. 7A/B positioning, as calculated using a finite elementsimulation.

FIGS. 9A and 9B depict the directions of the field lines of thelongitudinal field through the body and the lungs, respectively, for theFIG. 7A/B positioning.

FIGS. 10A and 10B depict inner and outer views, respectively, of anembodiment intended for delivering fields to a knee using two pairs oflongitudinal arrays.

Various embodiments are described in detail below with reference to theaccompanying drawings, wherein like reference numerals represent likeelements.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

The embodiments described below overcome the aforementioned limitationsof using A/P and R/L electrodes by including at least one pair ofelectrode arrays configured to generate a longitudinal field in thetarget region. Note that as used herein: (1) in the context of the headand main portion of the body, the longitudinal axis is perpendicular toboth the anterior-posterior axis and the lateral axis; (2) in thecontext of a leg or arm, the longitudinal axis is the proximal-distalaxis; (3) the term “longitudinal field” refers to a field which runs inthe same general direction as the longitudinal axis, and is not limitedto fields that are exactly parallel to the longitudinal axis; (4)electrode arrays designed to generate longitudinal fields are referredto as “longitudinal arrays”; and (5) conventional electrode arraysdesigned to generate fields that run generally between either the leftand right sides of the subject or the front and back of the subject arereferred to as “latitudinal arrays.”

To generate a longitudinal field, a pair of ring-shaped or arc-shapedelectrode arrays that fit around the subject's body may be used, withone array positioned above the other. In some embodiments, the arraysare designed as rings that completely surround the body part on whichthey are placed. In other embodiments, the arrays are designed as arcs(e.g., semicircles) that partially surround the body part on which theyare placed. When a voltage is applied between the upper and lowerelectrode arrays, the electric field that develops between them will belongitudinally oriented.

FIG. 2 is a schematic illustration depicting a first order estimate ofhow longitudinal fields can be generated in the body. In this example,we consider the electric field in a solid conducting cylindrical body 20when an AC voltage 25 is applied between thin ring-shaped electroderings 21, 22 on either end of the cylinder 20. It turns out that theresulting electric field in the cylinder 20 will be almost uniformlydirected longitudinally along the cylinder, as indicated by field lines26, and will also penetrate into the interior of the cylinder 20. Insome embodiments, the pair of electrode arrays for the delivery ofTTFields may be designed as two ring-shaped arrays that fit around thesubject's body, with one array placed above the other.

Using longitudinal fields can provide significant advantages becauseTTFields are more effective when they are parallel to the axis of celldivision. As a result, increasing the number of directions at which thefields are applied can increase the effectiveness against the tumor thatis being treated (in which the orientation of the cells during divisioncan vary). Notably, the use of longitudinal arrays opens up new optionsfor array layouts on the body that can optimize both field distributionand subject comfort.

FIGS. 3A-3D depict four examples of longitudinal pairs of electrodearrays designed to deliver TTFields to different parts of a person'sbody. In all of these embodiments, each of the electrode arrays includesone or more electrode elements mounted on a substrate that is configuredto hold the electrode elements against the subject's body so that theelectrode elements completely surround the respective body part. In somepreferred embodiments, the substrate is flexible in order to promoteconformance with the subject's body. An example of a suitable approachfor mounting individual electrode elements on a flexible substrate isdescribed below in connection with FIGS. 6A and 6B.

In the FIG. 3A embodiment, which is intended, e.g., for deliveringfields to the thorax or abdomen, the first electrode array is placed ata position 31 around the torso (e.g., just above the subject's waist),and the second electrode array is placed at a position 32 around thesubject's neck. In the FIG. 3B embodiment, which is intended, e.g., fordelivering fields to the abdomen, the first electrode array is placed ata position 33 around the torso (e.g., just above the subject's waist),and the second electrode array is placed at a position 34 around thetorso (e.g., at the top of the subject abdomen). In alternativeembodiments (not shown), e.g., for delivering fields to the lungs, thefirst electrode array is placed below the chest (similar to position 34in FIG. 3B) and the second electrode array is placed around thesubject's neck (similar to position 32 in FIG. 3A.

In the FIG. 3C embodiment, which is intended, e.g., for deliveringfields to a portion of the arm, the first electrode array is placed at aposition 35 on the arm that is proximal to the target region, and thesecond electrode array is placed at a position 36 on the arm that isdistal to the target region. Target regions within the elbow can beaccommodated by adjusting the location of these positions 35, 36.Similarly, in the FIG. 3D embodiment, which is intended, e.g., fordelivering fields to a portion of the leg, the first electrode array isplaced at a position 37 on the leg that is proximal to the targetregion, and the second electrode array is placed at a position 38 on theleg that is distal to the target region. Target regions within the kneecan be accommodated by adjusting the location of these positions 37, 38.

In the FIG. 3E embodiment, which is intended, e.g., for deliveringTTFields to the infratentorial brain, the brain stem, and to the neck,the first electrode array is placed at a position 26 around thesubject's neck, and the second electrode array is placed at a position27 that is close to the crown of the subject's head. In the FIG. 3Fembodiment, which is an alternative embodiment intended for deliveringfields to these same anatomic locations, the first electrode array isplaced at a position 28 around the subject's neck, and the secondelectrode array is placed at a position 29 on top of the subject's head.

Each of the embodiments depicted in FIGS. 3A-3E may be used forimplementing a method of treating a target region in a subject's bodywith TTFields by (1) affixing a first set of one or more electrodes tothe subject's body so as to surround a first part of the subject's bodyat a position that is longitudinally prior to the target region; (2)affixing a second set of one or more electrodes to the subject's body soas to surround a second part of the subject's body at a position that islongitudinally subsequent to the target region; and (3) applying a firstAC voltage with a frequency of 100-500 kHz between the first set of oneor more electrodes and the second set of one or more electrodes so as toimpose a first AC electric field with field lines that run through thetarget region longitudinally, the first AC electric field having a fieldstrength of at least 1 V/cm in at least a portion of the target region.In some preferred embodiments, the first and second sets of one or moreelectrodes our capacitively coupled to the subject body.

Depending on the anatomic location at which they are used, longitudinalarrays may provide one or more of the following advantages. First,longitudinal arrays may enable coverage of certain target regions withhigher field intensities than latitudinal arrays. For instance, whentreating lung tumors using only conventional latitudinal arrays, thearrays on the sides of the subject have to be positioned below thearmpits. As a result, the field intensity in the upper lobes of thelungs is relatively low. In contrast, longitudinal arrays positionedaround the waist and around the neck (as depicted in FIG. 3A) canprovide a more uniform high field intensity throughout the lungs (asdescribed below in connection with FIGS. 8 and 9A-9B).

Second, longitudinal arrays may adhere better to body contours thanlatitudinal arrays in certain anatomic locations. For example, whentreating the thorax, latitudinal arrays placed on the chest may notadhere well to body contours (e.g., in the case of female breasts),leading to sub-optimal electric contact of the arrays and the body,reducing field intensity in the tumor. In these situations, the electriccoupling of the field to the body through longitudinal arrays mayprovide better coverage than the electric coupling of the field to thebody through latitudinal arrays.

Third, large latitudinal arrays placed on the subject's body can limitmotion or cause discomfort to the subject in certain anatomic locations.For example, when treating the thorax, large latitudinal arrays placedon the subject's chest (e.g., as depicted in FIGS. 4A-4B) may causediscomfort or even limit motion. In these cases, using a pair ofproperly designed longitudinal arrays (e.g., as depicted in FIG. 3A) todeliver the field can help to improve comfort, because a longitudinalpair of arrays, with one array circumventing the neck and onecircumventing the upper abdomen or waist, can be more comfortable forthe subject to use.

A fourth significant advantage is that the electric fields that aregenerated using longitudinal arrays are roughly perpendicular to theelectric fields that are generated by latitudinal arrays (i.e.,anterior-posterior or laterally-positioned sets of electrode arrays).Arrays designed to create longitudinal fields (e.g., as depicted inFIGS. 3A-3D) can therefore be combined with conventional arrays designedto create latitudinal fields in order to treat the target region withfields at a plurality of different directions, which can increase theefficacy of the treatment. The availability of longitudinal arrays alsoprovides additional degrees of freedom for finding layouts for theelectrodes that optimize field distribution and subject comfort.

FIGS. 4A-4H depict examples in which a pair of longitudinal arrays(e.g., similar to those described above in connection with FIGS. 3A-F)are combined with a pair of latitudinal arrays. In each of thesesituations, after the electrodes are affixed at their respectivepositions, (a) an AC voltage is applied between the first and secondsets of electrodes that are arranged longitudinally in order to impose alongitudinal field in the target region, and (b) an AC voltage isapplied between the third and fourth sets of electrodes that arearranged latitudinally in order to impose a latitudinal field in thetarget region. These steps (a) and (b) are repeated in an alternatingsequence for the duration of the treatment, in order to repeatedlyswitch the direction of the field that is being imposed in the targetregion. In some embodiments, the switching rate is between 0.25 and 2seconds. Because treatment preferably proceeds for many hours at a time,each of these steps (a) and (b) is preferably repeated at least 10,000times. Preferably, the frequency of the AC voltages is between 100 and500 kHz, and in some preferred embodiments, the frequency is between 125and 250 kHz. In some preferred embodiments (e.g., for treatingpancreatic cancer and certain types of lung cancer), the frequency isbetween 140 and 160 kHz. In some preferred embodiments (e.g., fortreating ovarian cancer), the frequency is between 190 and 210 kHz.Preferably, each of the electric fields that is imposed in the targetregion has a field strength of at least 1 V/cm.

In the FIGS. 4A/B embodiment, which is intended, e.g., for deliveringfields to the thorax, the longitudinal array is implemented with thefirst electrode array placed at a position 31 just above the subject'swaist, and the second electrode array placed at a position 32 around thesubject's neck. And in addition, a latitudinal array is provided with athird electrode array placed at a position 41 on the subject's chest,and a fourth electrode array placed at a position 42 on the subject'sback. In this embodiment, the direction of the field lines of thelatitudinal field will run from front to back.

In the FIG. 4C/D embodiment, which is also intended, e.g., fordelivering fields to the thorax, the longitudinal array is implementedin the same way as in FIGS. 4A/4B, but the latitudinal array isimplemented with the third electrode array placed at a position 43 onthe subject's right side, and the fourth electrode array placed atposition 44 on the subject's left side. In this embodiment, thedirection of the field lines of the latitudinal field will run from sideto side.

In the FIG. 4E/F embodiment, which is also intended, e.g., fordelivering fields to the thorax, the longitudinal array is implementedin the same way as FIGS. 4A/4B, but the latitudinal array is implementedwith the third electrode array placed at a position 45 on the left sideof the subject's chest, and a fourth electrode array placed at position46 on the right side of the subject's back. In this embodiment, thedirection of the field lines of the latitudinal field will rundiagonally through the subject's chest from front to back.

In the FIG. 4G embodiment, which is intended, e.g., for deliveringTTFields to the infratentorial brain, the longitudinal array isimplemented with the first electrode array placed at a position 26around the subject's neck, and the second electrode array placed at aposition 27 that is close to the crown of the subject's head. And inaddition, a latitudinal array is provided with a third electrode arrayplaced at a position 47 on the left side of the subject's head, and afourth electrode array placed at position 48 on the right side of thesubject's head. In this embodiment, the direction of the field lines ofthe latitudinal field will run from side to side. Alternatively, thelatitudinal array may be provided using third and fourth electrodes (notshown) placed at positions on the front and back of the subject's head.

The FIG. 4H embodiment is similar to the FIG. 4G embodiment, except thatthe longitudinal array is implemented with the first electrode arrayplaced at a position 28 around the subject's neck, and the secondelectrode array placed at a position 29 on top of the subject's head.

Note that in addition to the embodiments described above in connectionwith FIGS. 4A-4H, a wide variety of alternative configurations thatcombine a pair of longitudinally positioned arrays with a pair oflatitudinally positioned arrays can be readily envisioned for use at awide range of anatomic locations, as will be apparent to persons skilledin the relevant arts.

FIGS. 5A-5D depict examples in which a pair of longitudinal arrays(e.g., similar to those described above in connection with FIGS. 3A-F)are combined with two pairs of latitudinal arrays. In each of thesesituations, (a) an AC voltage is applied between the first and secondset of electrodes that are arranged longitudinally in order to impose alongitudinal field in the target region, (b) an AC voltage is appliedbetween the third and fourth set of electrodes that are arrangedlatitudinally in order to impose a first latitudinal field in the targetregion; and (c) an AC voltage is applied between the fifth and sixth setof electrodes that are arranged latitudinally in order to impose asecond latitudinal field in the target region. The angle between thefirst latitudinal field and the second latitudinal field is preferablybetween 60° and 120°, and most preferably as close as possible to 90°.These steps (a), (b), and (c) are repeated in an alternating sequencefor the duration of the treatment, in order to repeatedly switch thedirection of the field that is being imposed in the target regionbetween each of the three directions. In some embodiments, the switchingrate is between 0.25 and 2 seconds. Because treatment preferablyproceeds for many hours at a time, each of these steps (a), (b), and (c)is preferably repeated at least 10,000 times.

In the FIG. 5A/B embodiment, which is intended, e.g., for deliveringfields to the thorax, the longitudinal array is implemented with thefirst electrode array placed at a position 31 just above the subject'swaist, and the second electrode array placed at a position 32 around thesubject's neck. In addition, a first latitudinal array is provided witha third electrode array placed at a position 41 on the subject's chest,and a fourth electrode array placed at a position 42 on the subject'sback, in order to generate a first latitudinal field with field linesthat run from front to back. Finally, a third latitudinal array isprovided with a fifth electrode array placed at position 51 on the rightside of the subject's body, and a sixth electrode array placed atposition 52 on the left side of the subject body, in order to generate asecond latitudinal field with field lines that run from side to side.

The FIG. 5C/D embodiment is similar to the FIG. 5A/B embodiment, exceptthat the third and fourth electrode arrays are placed at positions 55and 56 on the subject's front and back, respectively; and the fifth andsixth electrode arrays are placed at positions 57 and 58 on thesubject's front and back, respectively. In this embodiment, the firstlatitudinal field will have field lines that run from the front right tothe back left; and the second latitudinal field will have field linesthat run from the front left to the back right. The angle between thefirst latitudinal field and the second latitudinal field is preferablybetween 60° and 120°, and most preferably as close as possible to 90°.

Here again, in addition to the two embodiments described above inconnection with FIGS. 5A-5D, a wide variety of alternativeconfigurations that combine a pair of longitudinally positioned arrayswith two pairs of latitudinally positioned arrays can be readilyenvisioned for use at a wide range of anatomic locations, as will beapparent to persons skilled in the relevant arts.

The discussion of FIGS. 3-5 above explains the positions at which thevarious sets of electrodes are placed on the subject's body, but do notdescribe the construction of those sets of electrodes. A wide variety ofconstruction for implementing those sets of electrodes may be used,including but not limited to the configurations depicted in FIGS. 6A and6B.

FIG. 6A depicts a first configuration that is suitable for affixing aset of electrodes 60 to a subject's body. In this embodiment, each setof electrodes 60 includes a plurality of individual electrode elements61 mounted on a band-shaped substrate 62. The band -shaped substrate 62is shaped and dimensioned to fit on the particular body part where itwill be used. For example, for the longitudinal array depicted atposition 31 in FIG. 3A, the substrate 62 will be a flexible substratethat resembles a belt; for the longitudinal array depicted at position32 in FIG. 3A, the substrate 62 would be a flexible substrate thatresembles a choker; and for the longitudinal array depicted at position27 in FIG. 3E, the substrate 62 would be a flexible substrate thatresembles a headband; etc. The job of the substrate 62 is to hold theindividual electrode elements 61 against the subject's skin so thatthose elements make good contact the skin. Optionally, conductive gelmay be applied between the electrode elements 61 and the subject's skin.

In some embodiments, each of the individual electrode elements 61 is adisk-shaped capacitively coupled electrode with a high dielectricconstant, such as the electrode elements used in the conventionalNovocure TTF-100L transducer arrays. In alternative embodiments, insteadof using a plurality of individual electrode elements 61, a singleelectrode element (not shown) may be used, in which case the singleelectrode element is preferably either flexible or contoured to conformwith the particular portion of the subject's body where it will be used.

The individual electrode elements 61 within each set of electrodes 60are wired together using appropriate wiring 63. For example, theindividual electrode elements 61 may be wired in parallel, in series, orin a parallel/series combination. Optionally, this wiring 63 mayterminate at a connector 64. This connector 64 may be used to connectthe set of electrodes 60 with the AC signal generator 65, so that the ACsignal generator 65 can apply a voltage between two sets of electrodes.

FIG. 6B depicts a second configuration that is suitable for affixing apanel-shaped set of electrodes 60′ to a subject's body. Thisconfiguration includes a plurality of individual electrode elements 61mounted on a panel-shaped substrate 62′. The wiring 63 and connector 64in this FIG. 6B embodiment is similar to the corresponding elements inFIG. 6A. This FIG. 6B embodiment is best suited for placement atlocations 41-58 (depicted in FIGS. 4-5) and for generating the lateralfields described above in connection with those embodiments.

A wide variety of alternative substrate configurations for mounting aplurality of individual electrode elements will be apparent to personsskilled in the relevant arts, based on the anatomical position at whichthe electrode elements are positioned. FIGS. 7A-F depict the positioningof the electrode elements in three such configurations. The substratethat supports the electrode elements for the longitudinal sets ofelectrodes 71, 72 shown in FIGS. 7A/B (which depict front and backviews, respectively) will be similar to the band-shaped configurationshown in FIG. 6A, scaled to the appropriate size for the relevantanatomy. The substrate that supports the electrode elements for theanterior/posterior latitudinal sets of electrodes 73/74 depicted inFIGS. 7C/D (which depict front and back views, respectively) and for theright/left latitudinal sets of electrodes 75/76 depicted in FIGS. 7E/F(which depict front and back views, respectively), will be similar tothe panel-shaped configurations shown in FIG. 6B, scaled and shaped tothe appropriate size for the relevant anatomy. Combining all three ofthe electrode configurations FIGS. 7A/B, 7C/D, and 7E/F and cycling thefield between those three pairs of electrodes to provide three differentfield directions can provide excellent field coverage of the upper lobesof the lungs while maintaining patient comfort.

Finite element method calculations reveal that longitudinal arrays canprovide effective penetration of relevant anatomical structures. In oneexample, a plurality of ceramic disk-shaped electrode elements isdistributed at a first position 71 that corresponds to the waist and asecond position 72 that corresponds to the neck of a realisticcomputational phantom as depicted in FIGS. 7A/B.

FIG. 8 depicts the strength of the electric field for this example, ascalculated using a finite element simulation, for axial slices 81-86spaced at regular vertical intervals through the lungs. This simulationreveals that it is possible to obtain field intensities between 1-4 V/cmfield intensities throughout most of the lungs using longitudinalarrays. FIGS. 9A/B depict the directions 91 of the field lines of thelongitudinal field through the body and the lungs, respectively, forthis simulation. These figures show the longitudinal nature of thosefield lines.

In some cases, using at least one pair of longitudinal arrays may be theonly practical way to treat a tumor using TTFields. For instance, if atumor is located in a joint such as the knee or elbow, using onlylateral sets of electrodes could significantly hamper the subject'smobility.

FIGS. 10A and 10B depict inner and outer views, respectively, of anembodiment intended for delivering fields to a knee using two pairs oflongitudinal arrays, which overcomes this mobility problem. In thisembodiment, a first substrate holds a first set of one or moreelectrodes against the leg so that it partially surrounds the front sideof the leg at a position 101 that is proximal to the knee, a secondsubstrate holds a second set of one or more electrodes against the legso that it partially surrounds the back side of the leg at a position102 that is distal to the knee, a third substrate holds a third set ofone or more electrodes against the leg so that it partially surroundsthe back side of the leg at a position 103 that is proximal to the knee,and a fourth substrate holds a fourth set of one or more electrodesagainst the leg so it partially surrounds the front side of the leg at aposition 104 that is distal to the knee.

Each set of electrodes at positions 101-104 is preferably shaped like anopen arc that conform with the contours of the leg. This arc shape maybe achieved using flexible substrates upon which a plurality ofindividual electrode elements are mounted, as described above inconnection with FIG. 6A. Alternatively, the arc shape may be achievedusing a rigid substrate upon which one or more electrode elements aremounted. When the open arc configuration is used for the electrodearrays, it is important to place the arrays in any given pair onopposite aspects of the body part being used to ensure that the fieldpenetrates the body, because if both arcs in a given electrode pair areplaced on the same aspect on the body, then a significant electric fieldmay only develop in the superficial regions of the body.

In this embodiment, a first AC voltage is applied between the set ofelectrodes affixed at position 101 and the set of electrodes affixed atposition 102, resulting in an electric field with field lines that runin the general direction of the dashed line 106. Subsequently, a secondAC voltage is applied between the set of electrodes affixed at position103 and the set of electrodes affixed at position 104, resulting in anelectric field with field lines that run in the general direction of thedotted line 107. This configuration would result in two electric fieldsthat form an X-shape through the joint. Although the directions of thesetwo fields (106, 107) may not be perpendicular, the angle between thosefields will be sufficiently large to provide improved results withrespect to a single-direction field. Preferably, the frequency of thefirst and second AC voltages is between 100 and 500 kHz. In somepreferred embodiments, this frequency is between 125 and 250 kHz.Preferably, the strength of the two electric fields is at least 1 V/cmin at least a portion of the target region.

In alternative embodiments, a knee may be treated by combining one pairof longitudinal arrays positioned above and below the joint with onepair of latitudinal arrays placed on the lateral sides of the joint. Inthese embodiments, the longitudinal arrays may completely surround theleg (e.g., as seen in FIG. 3D) or may partially surround the leg (e.g.,as described above in connection with FIG. 10).

Note that the same concepts described above in connection with FIG. 10in the context of a knee can also be applied in the context of an elbowor to other joints if appropriate changes to the relevant dimensions aremade.

Note that in some cases (e.g., the FIG. 3A-3F embodiments), the arraysare designed to completely circumvent the body part on which they areplaced, and in other cases (e.g., the FIG. 10A-B embodiments), thearrays are designed as open arcs that do not completely circumvent thebody part on which they are is placed. But in both of those arrayconfigurations, each of the arrays must be positioned at a differentposition along the longitudinal axis.

TTFields may be delivered through electrode arrays that capacitivelycouple the electric field generated by a field generating device intothe body. For instance, the array design structure described in U.S.Pat. No. 7,715,921, could be incorporated into the design oflongitudinal arrays. The electrode arrays could also be designed as acomposite electrode comprising a plurality of ceramic elements that aredesigned to be positioned against the subject's skin as described inU.S. Pat. No. 8,715,203.

In some embodiments, the arrays are designed as a set of ceramic diskswith a high dielectric constant which are connected to the body via athin conductive gel. The disks in each array are electricallyinter-connected via a flex wire, and an adhesive tape is placed abovethe disks so that the array adheres firmly to the subject's body. Thecomponents for creating the longitudinal arrays may be similar to thosethat are currently used to deliver TTFields to the head using Optune™,as well as to deliver TTFields to the torso using the NovoTTF-100L. Theceramic elements can be wired in parallel, in series, or in anycombination of parallel and series (e.g., 3 groups wired in parallel,where each group includes 3 disks wired in series.

Optionally, the design of the array layout could be performed with theassistance of finite element simulations, which could be used tocalculate the expected field distribution that any specific design oflongitudinal arrays will yield. Such designs may be optimized to delivera maximal field intensity to a target region.

Optionally, the disks in each array may be connected in a manner thatenables them to be fitted to subjects of different sizes (e.g., eacharray may comprise several connected patches with a small number ofdisks, or the disks may be connected with flexible connectors).

While the above embodiments are described in the context of a humansubject, they may also be used for other animals (e.g., dogs, horses,etc.) by making appropriate modifications, which will be apparent topersons skilled in the relevant arts.

While the present invention has been disclosed with reference to certainembodiments, numerous modifications, alterations, and changes to thedescribed embodiments are possible without departing from the sphere andscope of the present invention, as defined in the appended claims.Accordingly, it is intended that the present invention not be limited tothe described embodiments, but that it has the full scope defined by thelanguage of the following claims, and equivalents thereof.

What is claimed is:
 1. An apparatus for treating a target region in alimb of a subject's body with TTFields, the apparatus comprising: afirst set of one or more capacitively coupled electrodes; a firstsubstrate configured to hold the first set of one or more electrodesagainst the subject's body so that the first set of one or moreelectrodes partially surrounds a first side of the limb at a positionthat is proximal to the target region; a second set of one or morecapacitively coupled electrodes; a second substrate configured to holdthe second set of one or more electrodes against the subject's body sothat the second set of one or more electrodes partially surrounds asecond side of the limb at a position that is distal to the targetregion, wherein the second side of the limb is opposite to the firstside of the limb; a third set of one or more capacitively coupledelectrodes; a third substrate configured to hold the third set of one ormore electrodes against the subject's body so that the third set of oneor more electrodes partially surrounds the second side of the limb at aposition that is proximal to the target region; a fourth set of one ormore capacitively coupled electrodes; and a fourth substrate configuredto hold the fourth set of one or more electrodes against the subject'sbody so that the fourth set of one or more electrodes partiallysurrounds the first side of the limb at a position that is distal to thetarget region.
 2. The apparatus of claim 1, further comprising an ACvoltage generator configured to generate, in a repeating and alternatingsequence, (a) a first AC voltage with a frequency of 100-500 kHz betweenthe first set of one or more electrodes and the second set of one ormore electrodes, and (b) a second AC voltage with a frequency of 100-500kHz between the third set of one or more electrodes and the fourth setof one or more electrodes.
 3. The apparatus of claim 2, wherein each ofthe first and second AC voltages has a frequency of 125-250 kHz.
 4. Theapparatus of claim 1, wherein each of the first, second, third, andfourth sets of one or more electrodes comprises a plurality of flatelectrode elements.
 5. The apparatus of claim 4, wherein each of thefirst, second, third, and fourth substrates is flexible.
 6. Theapparatus of claim 1, wherein the limb is an arm having an elbow,wherein each of the first and third substrates is shaped and dimensionedto fit on the arm proximally with respect to the elbow, and wherein eachof the second and fourth substrates is shaped and dimensioned to fit onthe arm distally with respect to the elbow.
 7. The apparatus of claim 1,wherein the limb is a leg having a knee, wherein each of the first andthird substrates is shaped and dimensioned to fit on the leg proximallywith respect to the knee, and wherein each of the second and fourthsubstrates is shaped and dimensioned to fit on the leg distally withrespect to the knee.
 8. A method of treating a target region in a limbof a subject's body with TTFields, the method comprising: affixing afirst set of one or more electrodes so as to partially surround a firstside of the limb at a position that is proximal to the target region;affixing a second set of one or more electrodes so as to partiallysurround a second side of the limb at a position that is distal to thetarget region, wherein the second side of the limb is opposite to thefirst side of the limb; affixing a third set of one or more electrodesso as to partially surround the second side of the limb at a positionthat is proximal to the target region; affixing a fourth set of one ormore electrodes so as to partially surround the first side of the limbat a position that is distal to the target region; applying a first ACvoltage with a frequency of 100-500 kHz between the first set of one ormore electrodes and the second set of one or more electrodes so as toimpose a first AC electric field through the target region, the first ACelectric field having a field strength of at least 1 V/cm in at least aportion of the target region; and applying a second AC voltage with afrequency of 100-500 kHz between the third set of one or more electrodesand the fourth set of one or more electrodes so as to impose a second ACelectric field through the target region, the second AC electric fieldhaving a field strength of at least 1 V/cm in at least a portion of thetarget region, wherein the steps of applying the first AC voltage andapplying the second AC voltage are performed in a repeating andalternating sequence.
 9. The method of claim 8, wherein each of thefirst, second, third, and fourth sets of one or more electrodes iscapacitively coupled to the subject's body.
 10. The method of claim 9,wherein each of the first and second AC voltages has a frequency of125-250 kHz.
 11. The method of claim 8, wherein the steps of applyingthe first AC voltage and applying the second AC voltage are repeated atleast 10,000 times in an alternating sequence.
 12. The method of claim8, wherein the limb is an arm having an elbow, wherein the first set ofone or more electrodes and the third set of one or more electrodes arepositioned proximally with respect to the elbow, and wherein the secondset of one or more electrodes and the fourth set of one or moreelectrodes are positioned distally with respect to the elbow.
 13. Themethod of claim 8, wherein the limb is a leg having a knee, wherein thefirst set of one or more electrodes and the third set of one or moreelectrodes are positioned proximally with respect to the knee, andwherein the second set of one or more electrodes and the fourth set ofone or more electrodes are positioned distally with respect to the knee.14. The method of claim 8, wherein each of the first, second, third, andfourth sets of one or more electrodes comprises a plurality of flatelectrode elements.